The HNRC will focus broadly on the shifting phenomenology and course of neuroAIDS and
neuroAIDS in resource-limited settings.
Shifting Phenomenology and Course of NeuroAIDS
In the developed world, every year new antiviral treatments have emerged, targeting multiple pathways involved in HIV pathogenesis. These therapies have had the effect of transforming what was once a debilitating, and often rapidly fatal, disease into a chronic infection with which many people survive for very long periods of time often with minimal or only modest medical symptoms.The effect on the neurobehavioral complications associated with HIV has been a reduction in incidence of debilitating forms of dementia, although the same cannot be said for milder forms of neurocognitive impairment (NCI). Importantly, results from HNRC and several other cohort studies indicate that there may be various presentations of HIV associated neurocognitive disorder in the era of HAART. While different investigators have used slightly different terminology, there is an emerging view that at least the following patterns may be seen: (a) a mild form of neurocognitive disorder that reverses with ARV treatment either permanently, or at least for a very long time; (b) a relapsing-remitting form akin to demyelinating disorders wherein persons may have mild impairment at initial presentation, then normalize, and subsequently again become impaired; (c) a long-term static impairment of variable severity, generally mild; (d) a sub-group of individuals who manifest steady, slow deterioration, or deterioration after a period of stability; and (e) a small number of cases who manifest rapid, catastrophic decline, generally after ARV treatment options have been exhausted or, occasionally, via an immune reconstitution linked pathogenesis.
This shift in the phenomenology and course of neuroAIDS, as it has been influenced by treatment, raises new questions about the role of viral and host factors, and their interactions in HIV neuropathogenesis. HNRC studies suggest that co-factors such as the rising epidemic of methamphetamine abuse and frequent co-infection with viruses such as Hepatitis C may contribute both to the onset and chronicity of HIV-associated neurocognitive disorders. Defining optimum treatments that target these neurological complications is another challenge and requires development of improved techniques that track the progress of HIV CNS disease—e.g., development of more specific plasma or CSF markers, more sensitive functional and structural imaging methodologies, or neurocognitive and neuromotor assessment techniques. A related challenge is determining what therapeutic strategies have specificity for CNS complications and require studies of factors such as CNS penetrance of agents, their potential unique effects on HIV and cellular hosts within the CNS compartment, and possible host genetic influences on pharmacokinetics and pharmacodynamics.
A second area of intense focus has to do with early HIV infection. With the development of practicable methods for identifying HIV infection before the traditional antibody test becomes positive (pooled RNA) it may be possible to treat individuals at a time when their viremia is high and they may be arguably the most infectious. An earlier HNRC study found that degree of immunosuppression and plasma viral load in the early phase of infection predicted likelihood of developing NCI. Thus, a critical question is whether identification and treatment of acutely infected cases could prevent developing neurocognitive complications. To address this question one of the priorities of the HNRC is to enrich its patient cohort with acute and early infection cases that receive comprehensive neuromedical and neuropsychological examination early, establishing a baseline for follow up.
NeuroAIDS in Resource-Limited SettingsWhile it is anticipated that ART will become more available globally, economic constraints and sociocultural factors may continue to limit access, or result in suboptimal treatment (limitations on types or quantities of drugs; unplanned treatment interruptions due to limitations in public health systems). The role of host and viral factors, as well as various comorbidities (e.g., nutritional deficiencies; co-infection with viral, bacterial, and protozoal disease) in influencing the development and progression of neuroAIDS is basically unknown.
While it may be the case that many of the insights about HIV neuropathogenesis may be translated to the international setting, it is also likely that we will find significant differences, whose appreciation will be necessary to respond to the challenges of neuroAIDS in other parts of the world. For example, focusing on the “virus” side of the host-virus equation, most research in the developed world has focused on HIV clade B. Elsewhere other clades predominate, particularly clade C in India and Eastern and Southern Africa and parts of China, and clade F in some parts of Eastern Europe such as Romania. One aim of the HNRC during this renewal period will be to identify colleagues in various resource-limited settings with whom we can collaborate to develop local expertise in neuroAIDS research that can then develop into systematic, hypothesis-driven studies.